title: Fibroblast growth factor receptor-3 (FGFR-3) regulates expression of paneth cell lineage-specific genes in intestinal epithelial cells through both TCF4/beta-catenin-dependent and -independent signaling pathways.
abstract: Fibroblast growth factor receptor-3 (FGFR-3) expression in the developing intestine is restricted to the undifferentiated epithelial cells within the lower portion of the crypt. We previously showed that mice lacking functional FGFR-3 have a significant decrease in the number of Paneth cells in the small intestine. Here, we used Caco2 cells to investigate whether FGFR-3 signaling can directly modulate expression of Paneth cell differentiation markers through its effects on TCF4/β-catenin or through other signaling pathways downstream of this receptor. Caco2 cells treated with FGFR-3 ligands or expressing FGFR-3(K650E), a constitutively active mutant, resulted in a significantly increased expression of genes characteristic of mature Paneth cells, including human α-defensins 5 and 6 (HD5 and HD6) and Paneth cell lysozyme, whereas enterocytic differentiation markers were reduced. Activation of FGFR-3 signaling sustained high levels of β-catenin mRNA expression, leading to increased TCF4/β-catenin-regulated transcriptional activity in Caco2 cells. Sustained activity of the TCF4/β-catenin pathway was required for the induction of Paneth cell markers. Activation of the MAPK pathway by FGFR-3 is also required for the induction of Paneth cell markers in addition to and independent of the effect of FGFR-3 on TCF4/β-catenin activity. These studies suggest that coordinate activation of multiple independent signaling pathways downstream of FGFR-3 is involved in regulation of Paneth cell differentiation.
authors.affiliation: Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Brooks
authors.initials: B
authors.lastname: Brodrick
authors.forename: Alda
authors.initials: A
authors.lastname: Vidrich
authors.forename: Edith
authors.initials: E
authors.lastname: Porter
authors.forename: Leigh
authors.initials: L
authors.lastname: Bradley
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Buzan
authors.forename: Steven M
authors.initials: SM
authors.lastname: Cohn
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020125:Mutation, Missense; D009928:Organ Specificity / Q000502:physiology; D019879:Paneth Cells / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C500225:DEFA5 protein, human; C517765:DEFA6 protein, human; C532096:TCF4 protein, human; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D014157:Transcription Factors; D023084:alpha-Defensins; D051176:beta Catenin; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3